This invention relates to the field of hemostatic devices for controlling bleeding.
Uncontrolled bleeding can result in shock and death. In surgical patients and patients receiving anticoagulant medication, the problem of rapid blood loss arising from, for example, a hemorrhage of a blood vessel, body tissue, organ or bone can give rise to a life threatening situation.
Biodegradable devices for controlling bleeding are commercially available. However, many of these devices require the impregnation of protein agents such as thrombin or fibrinogen to be effective. Unfortunately, special storage conditions are required to preserve the hemostatic activity of these protein agents. For example, many of these devices must be stored under refrigeration conditions to maintain the bioactivity of the hemostatic devices into which the protein agents have been impregnated. Such requirements prohibit certain field applications of the patch, where refrigeration facilities are unavailable. Another problem with certain commercially available hemostatic devices is their lack of flexibility in the dry state. Many hemostatic devices do not conform easily to the shape of the body surface to which it is applied. In addition, hemostatic devices which further include hemostatic agents, such as thrombin, typically require that the thrombin be reconstituted and added to the dry devices immediately before use to provide a flexible hemostatic device having sufficient hemostatic activity to control bleeding.
The invention provides a hemostatic device which solves the above-described and other problems of the prior art devices. Methods for preparing the hemostatic devices of the invention also are provided. The hemostatic devices of the invention do not require exogenously added protein agents to be effective. Accordingly, the hemostatic devices of the invention can withstand elevated temperatures and do not require refrigeration to retain hemostatic efficacy. In addition, the hemostatic devices disclosed herein are easy to use and mold easily to body contours. Accordingly, the hemostatic devices of the invention are particularly useful for treating the problematic hemorrhages of parenchymal organs, spine, and brain. Such hemostatic devices can be sterilized and packaged in a sterile package for pharmaceutical applications.
According to one aspect of the invention, a process for preparing a hemostatic device of the invention is provided. The process involves: (a) suspending a plurality of collagen particles in water to form a collagen slurry, wherein the collagen particles have a bulk density sufficient to form a suspension in water and wherein the collagen slurry has a concentration in the range of about 1% to about 2% (weight/volume); and (b) lyophilizing (freeze-drying) the collagen slurry to form a hemostatic device. The hemostatic devices that are formed in accordance with this method are foams, preferably reticulated open cell foams. Foams also are referred to in the art as xe2x80x9cspongesxe2x80x9d. Preferably, the collagen particles of the hemostatic device have a hemostatic activity that is equivalent to the hemostatic activity of the collagen particles from which the hemostatic device is formed. More preferably, the hemostatic devices are formed of Avitene(copyright) flour and the collagen particles of the hemostatic devices of the invention have a hemostatic activity equivalent to the hemostatic activity of Avitene(copyright) flour.
Hemostasis is a term of art which refers to cessation of bleeding. Although not wishing to be bound to any particular theory or mechanism, it is believed that avoiding contact between the collagen particles and an acid solution and minimizing exposure of the collagen to denaturing conditions, such as excessive mechanical shear, high temperature, or long H2O residence times, during the fabrication process results in a greater retention of hemostatic activity by the collagen particles compared to particles which are subjected to such denaturing conditions. Accordingly, the hemostatic devices of the invention have a greater hemostatic activity compared to conventional collagen hemostatic devices in which the fabrication process has involved dissolution of collagen in acid solution.
In one embodiment of the invention, the method for forming a hemostatic device of the invention involves suspending a plurality of collagen particles (preferably, collagen fibrils) in water to form a collagen slurry and subjecting the collagen slurry to lyophilization (freeze-drying) to form the hemostatic device. The collagen particles have a bulk density sufficient to form a suspension in water. In general, the bulk density of the collagen particles is in the range of about 1.5 to about 3.5 lbs/ft3 and, more preferably, from about 2 to about 3 lbs/ft3. The particles are suspended in water to obtain a collagen concentration in the range of about 1% to about 2% (weight/volume), and, more preferably, in the range of about 1.1% to about 1.64% (weight/volume). In the preferred embodiments, the hemostatic devices are formed of collagen particles that have not been subjected to acid dissolution or other denaturing conditions.
According to yet another aspect of the invention, a product prepared by the above-described process is provided. A particular embodiment of this process in provided in the Examples. The process, optionally, further includes the step of cross linking the collagen within the hemostatic devices of the invention, e.g., by heating the collagen fibers of the invention at a temperature and for a period of time sufficient to form crosslinks, preferably, without substantially reducing the hemostatic activity of the collagen fiber. Preferably, the crosslinked hemostatic devices retain at least about 80%, more preferably, at least about 90% and, most preferably, at least about 95% hemostatic activity compared to the hemostatic activity of the hemostatic device prior to crosslinking.
In certain preferred embodiments, the hemostatic device is formed of collagen particles that have a hemostatic activity equivalent to the hemostatic activity of the collagen particles from which the device is formed. In the preferred embodiments, the hemostatic device is formed of collagen flour, preferably Avitene(copyright) flour, that has not been subjected to acid dissolution. In these and other embodiments, the hemostatic device preferably has a density of from about 0.015 to about 0.023 gm/cc; and/or a weight percent solids ranging from about 1.10 to about 1.64 weight percent.
In yet other embodiments, the hemostatic device of the invention is formed of collagen and has a hemostatic activity in a pig spleen animal model of hemostasis that corresponds to one tamponade for a hemostatic device having a thickness of xe2x85x9c inch, a length of xc2xd inch, and a width of xc2xd inch. An exemplary pig spleen animal model of hemostasis is provided in the Examples.
In certain embodiments, the hemostatic devices of the invention further include a hemostasis-promoting amount of at least one hemostatic agent. As used herein, a xe2x80x9chemostasis-promoting amountxe2x80x9d is the amount effective to accelerate clot formation at an interface between a surface (e.g., of a wound or lesion) and the hemostatic device. Exemplary hemostatic agents include a thrombin molecule, a fibrinogen molecule, a source of calcium ions, an RGD peptide, protamine sulfate, an epsilon amino caproic acid, and chitin. In the preferred embodiments, the hemostatic agent is thrombin. The hemostatic agents can be introduced into the hemostatic devices at any stage during the preparation of these devices, including adding the hemostatic agent to the collagen slurry, lyophilizing the agents into the hemostatic device during its preparation or applying the agents to the device post-processing.
In certain embodiments, the hemostatic devices of the invention further include a therapeutically effective amount of at least one therapeutic agent, such as agents which promote wound-healing and or reduce pain (e.g., vascular pain). Agents which promote wound-healing and/or reduce pain include anti-inflammatory agents (steroidal and non-steroidal) such as agents which inhibit leukocyte migration into the area of surgical injury, anti-histamines; agents which inhibit free radical formation; and bacteriostatic or bacteriocidal agents.
Various additives, optionally, can be incorporated into the hemostatic devices of the invention without substantially reducing the hemostatic activity of these devices. The term xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term xe2x80x9ccarrierxe2x80x9d denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the collagen fibrils of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired hemostatic activity.
The hemostatic devices of the invention preferably have one or more mechanical (e.g., tensile strength, wettability) and/or functional (hemostatic activity) properties that are equivalent to or greater than those of commercially available hemostatic devices, such as Gelfoam(copyright) 100 (Upjohn Company), Actifoam(copyright) (Davol Inc., Cranston, R.I.) and Helistat(copyright) (Johnson and Johnson Medical Inc., Arlington, Tex.). Gelfoam(copyright) is an absorbable gelatin sponge and is described in U.S. Pat. No. 2,465,357. Actifoam(copyright) is a crosslinked collagen sponge and is described in U.S. Pat. Nos. 4,953,299 and 5,331,092. Helistat(copyright) is an absorbable collagen sponge that is formed of tendon collagen.
The hemostatic devices of the invention can be formed into a variety of shapes. In certain embodiments, the hemostatic device is in the form of a flexible sheet which, optionally, is packaged in a sterile package. More complex shapes also are contemplated.
The hemostatic devices of the invention are useful for promoting hemostasis at a site of bleeding (e.g., reducing or eliminating bleeding from a wound). Accordingly, a further aspect of the invention involves methods for promoting hemostasis. In general, such methods of the invention involve manually pressing a hemostatic device of the invention against a bleeding surface, such as a surface of a wound or a surface of a lesion on an organ, tissue or other bleeding surface of, e.g., a parenchymal organ (e.g., spleen, liver, lung or pancreas), a spine, a brain, for a period of time until clotting has occurred at the interface between the hemostatic device and the surface.
A number of embodiments of the invention are summarized above. However, it should be understood that the various limitations presented in each embodiment are not mutually exclusive and, accordingly, the limitations can be combined to obtain further aspects of the invention.